The present invention relates to a method for making tablets, and more particularly, relates to a method for making tablets that are substantially free of excipients, where at least one therapeutic compound in the tablet serves as a compaction enhancing agent for the tablet. The present invention also relates to tablet compositions produced by the methods of the present invention.
Tablet compositions are commonly used to deliver therapeutic compounds to a patient such as a human or animal. By xe2x80x9ctabletxe2x80x9d as used herein, it is meant solid particles, containing or including therapeutic compounds, that are compressed under pressure into any desirable shape, such as a pill or caplet.
Typically, tablets contain other ingredients, hereinafter referred to as xe2x80x9cexcipients,xe2x80x9d that provide necessary physical or aesthetic properties to a tablet for delivery of the therapeutic compound. For example, with respect to physical properties, tablets generally need to have acceptable hardness, disintegration, dissolution rate for release of the therapeutic, friability, stability, and size to effectively deliver a therapeutic compound. With respect to aesthetics, it may be desirable for the tablet to contain additives that appeal to the human senses such as colorants, fragrances, texture modifiers, and/or flavorants. Specific types of excipients commonly used in tablet compositions include for example diluents, binders, lubricants, glidants, disintegrants, gelling agents, flavoring agents, and coloring agents. Many of these excipients are commonly added because the therapeutic compound alone may have poor compactability, and thus excipients are needed to achieve the desired tabletting performance.
A problem, however, in using excipients, is that the tablet may become too large to ingest due to the amount of excipients needed to effectively formulate the tablet. A solution to this problem would be to reduce the amount of therapeutic compound and excipients to reduce the overall weight of the tablet, however, multiple tablets would then be needed to deliver the appropriate amount of therapeutic compound. Another problem in using excipients is that, particularly in nutraceuticals, they do not adequately compensate for low density of many herbal products and as such, are in many cases unsatisfactory solutions to tabletting problems. Additionally, excipients often add cost to the tablet, and also may be objectionable to some consumers.
Tablet formulations in which it is especially desirable to reduce the amount of excipients are those used for the treatment of connective tissue to prevent, repair, or lessen ailments of the joints and cartilage tissue, such as observed with arthritis. For example, U.S. Pat. Nos. 5,364,845 and 5,587,363 both to Henderson (xe2x80x9cHendersonxe2x80x9d) disclose therapeutic compositions for the treatment and repair of connective tissue containing amino sugars such as glucosamine, and glycosaminoglycans such as chondroitin. The compositions disclosed in Henderson are used in the form of a powder (for large animals) or capsule (for small animals). Additionally, it is known that these same compositions can be supplied in tablet form, if excipients are used. For example, the commercially available product called xe2x80x9cOsteo-Bi-flexxe2x80x9d supplied by Rexall Sundown, provides in tablet form a composition containing glucosamine, chondroitin sulfate, and excipients, where the excipients make up at least 23 wt % of the tablet formulation.
U.S. Pat. No. 5,843,919 to Burger discloses a composition and method for the treatment of arthritis where the composition contains one or more glucosamines and one or more omega-3-fatty acids. Although Burger discloses that a tablet can be prepared, it is apparent that excipients would be needed as Burger discloses that the glucosamine is preferably dissolved in an oil containing the omega-3-fatty acid.
Other compositions, which may optionally be in the form of tablets, for treating ailments of the joints and connective tissues are disclosed in for example U.S. Pat. No. 5,605,891 to Prino et al., U.S. Pat. No. 5,840,715 to Florio, and U.S. Pat. No. 5,849,336 to Aoyagi et al. These patents however, provide no specific example of useful tablet formulations.
Amino sugars and glycosaminoglycans have also been used in compositions for treating skin. For example, U.S. Pat. No. 5,804,594 to Murad discloses a composition for the prevention and treatment of skin conditions that contain a sugar compound, an antioxidant, an amino acid, a transition metal component, a catechin based preparation, a glucosamine and chondroitin. Although tablet formulations are disclosed, it is taught that such compositions need to be prepared in the presence of carriers.
With respect to other therapeutics, it is known that a therapeutic alone may be compressible, without excipients. For example, U.S. Pat. No. 5,079,007 to Putnam discloses an implant containing a crystalline salt of cephalosporin, an amorphous salt of cephalosporin and from 0 to 10 weight percent excipients. Putnam teaches that the crystalline and amorphous cephalosporin forms are compressible alone to form a tablet, and that the ratio of the two components are adjusted to obtain the desired release characteristics of the implant. Putnam thus does not describe a method for making a tablet where one therapeutic compound serves as a compaction enhancing agent for a different therapeutic compound.
Thus, it would be desirable to develop a method of making tablets and tablet compositions produced therefrom that are substantially free of excipients, where at least one of the therapeutic compounds is a compaction enhancing agent for the other therapeutic compound.
The present invention provides a method of making tablets that are substantially free of excipients. The method of the present invention includes forming a compactable granular mixture comprising (i) at least about 3 weight percent of a compaction enhancing therapeutic compound, (ii) at least one other therapeutic compound that is different from the compaction enhancing therapeutic compound and (iii) less than about 15 weight percent of non-aesthetic excipients. The compactable granular mixture is compressed to form one or more tablets.
In a preferred embodiment of the present invention, the compaction enhancing therapeutic compound includes a glycosaminoglycan and the other therapeutic compound includes an amino sugar.
The present invention also provides a tablet composition containing from about 3 weight percent to about 99.5 weight percent of a compaction enhancing therapeutic compound; from about 0.5 weight percent to about 97 weight percent of at least one second therapeutic compound that is different from the compaction enhancing therapeutic compound; and less than about 15 weight percent excipients. The compaction enhancing therapeutic compound enhances the compaction of the second therapeutic compound and is preferably in intimate admixture with the second therapeutic compound.
The present invention provides a method of making tablets that are substantially free of excipients. The tablets produced by the method of the present invention contain at least two therapeutic compounds, where at least one of the therapeutic compounds serves as a compaction enhancing agent for the other therapeutic compound. By being able to provide tablets that are substantially free of excipients, smaller tablets and/or tablets containing greater amounts of therapeutic compounds can be produced. Thus, tablets can be provided that are more easily ingested due to the smaller size, and/or eliminating the need for taking multiple tablets to obtain a desired dosage of a therapeutic compound.
By xe2x80x9csubstantially freexe2x80x9d of excipients it is meant that the tablet contains less than about 15 weight percent, more preferably less than about 8 weight percent, and most preferably less than about 2 weight percent excipients, based on the total weight of the tablet on a dry basis (i.e., excluding moisture as hereinafter defined). The term xe2x80x9cexcipient,xe2x80x9d as used herein refers to any additive, liquid or solid, present in the tablet that provides some non-therapeutic property to the tablet. For example, excipients are usually added to enhance mechanical or aesthetic properties in a tablet, or to dilute the therapeutic compound. As such, the term excipient, as used herein, does not include therapeutic compounds, or moisture, such as water or other solvent, that is used during the manufacture of the tablet, or is inherently present in one of the ingredients used to form the tablet. Common mechanical excipients include for example binding agents, lubricants, disintegrants, coating agents, gelling agents, glidants, absorbents, surfactants, antiadherents, or combinations thereof. Common aesthetic excipients include for example colorants, flavorants, or combinations thereof Common excipients used to dilute the therapeutic compound include for example diluents, fillers, or combinations thereof. Preferably, the tablet contains less than about 15 wt %, more preferably less than 8 wt %, and most preferably less than about 2 wt % mechanical or diluting excipients (i.e., non-aesthetic excipients) based on the total weight of the tablet on a dry basis.
By xe2x80x9ctherapeutic compoundxe2x80x9d it is meant any substance used to treat (including prevent, diagnose, alleviate, or cure) a malady, affliction, nutritional deficiency, disease or injury in a patient. The term xe2x80x9ctherapeutic compoundxe2x80x9d is also meant to include substances that are a supplement for improving the nutritional, physical, or emotional well being of a patient such as vitamins, minerals, or herbal based supplements. By xe2x80x9cpatientxe2x80x9d it is meant a human and/or animal such as a mammal or reptile.
In the method of the present invention, a compactable granular mixture is formed containing (i) at least about 3 weight percent of a compaction enhancing therapeutic compound, (ii) at least one other therapeutic compound that is different from the compaction enhancing therapeutic compound and (iii) less than about 15 weight percent of non-aesthetic excipients. The compactable granular mixture is then compressed to form one or more tablets.
The compaction enhancing therapeutic compound is any therapeutic compound that enhances the compactability of the other therapeutic compound. By xe2x80x9cenhances the compactabilityxe2x80x9d it is meant that when the compaction enhancing therapeutic compound is mixed in the amounts (i.e., at least 3 weight percent) and manner (such as for example granulating, solvent dissolution and removal, or blending) as described herein with the other therapeutic compound, and optional lubricant, the granular mixture formed can be compressed into a tablet having acceptable friability (i.e., about 1% or less), and an increased hardness of at least about 10%, more preferably at least about 20%, and most preferably 50%, based on a tablet of the same weight, shape, and size, compressed under the same conditions, and not containing the compaction enhancing therapeutic compound. Hardness and friability can be determined by those techniques described hereinafter.
Preferably, the amount of compaction enhancing therapeutic compound in the tablet is at least about 3 weight percent to about 99.5 weight percent, more preferably from about 5 weight percent to about 50 weight percent and most preferably from about 5 weight percent to about 15 weight percent, based on the total tablet weight.
Examples of compaction enhancing therapeutic compounds include for example glycosaminoglycans such as heparin, dermatan sulfate, chondroitin, or sulodexide; herbal or botanical based extracts such as St. John""s Wort extract, horse chestnut, ginseng, ginko biloba, kelp, grape seed extract; vitamins such as niacinamide ascorbate, and derivatives thereof; salt forms of minerals; anti-inflammatory agents such as naproxen; antibiotics such as cephalosporin; cholesterol lowering agents such as cholestyramine; pharmaceutically acceptable salts of any of the foregoing; or any combination thereof.
In a preferred embodiment of the present invention, the compaction enhancing therapeutic compound is a glycosaminoglycan such as chondroitin, derivatives of chondroitin, including pharmaceutically acceptable salts thereof; an herbal or botanical extract such as St. John""s Wort extract, or grape seed extract; or combinations thereof.
The tablet also contains at least one other therapeutic compound that is different from the compaction enhancing therapeutic compound. This other therapeutic compound may be any therapeutic compound known to those skilled in the art. For example, the other therapeutic compound may be a compaction enhancing therapeutic compound as previously described herein, or a compound that does not enhance compaction (i.e., a non-compaction enhancing therapeutic compound).
Examples of therapeutic compounds that may be used as the other therapeutic compound include anti-inflammatory agents; antibiotics; cholesterol lowering agents; antifungal agents; antineoplastic agents; analgesics; hormones; peptides; anticoagulation agents; circulatory drugs; antianginals; antituberculars; antivirals; narcotics; sedatives; diet products; nutritional supplements such as vitamins or minerals; herbal or botanical extracts; anti-smoking libido agents; amino acids, aminosugars; pharmaceutically acceptable salts or derivatives of any of the foregoing; or any combination thereof. Specific examples of vitamins and minerals useful as the other therapeutic compound include Vitamin C, dried powder forms of Vitamin A, Vitamin D, Vitamin E, Vitamin K, or beta carotene; B vitamins, such as thiamin, riboflavin, niacin, Vitamin B6, Vitamin B12, biotin, or folic acid; pantothenic acid, calcium, iron, zinc, iodine, magnesium, zinc, selenium, copper, manganese, chromium, molybdenum, potassium, boron, nickel, silicon, tin, vanadium; derivatives or salts of the foregoing; or combinations thereof. Examples of herbal or botanical extracts useful as the other therapeutic compound in the present invention include St. John""s Wort extract, horse chestnut, ginseng, ginko biloba, kelp, grape seed extract or combinations thereof.
In a preferred embodiment of the present invention, the other therapeutic compound is a therapeutic compound that does not enhance the compactability of another therapeutic compound. Examples of therapeutic compounds that do not enhance the compactability of a therapeutic compound include for example aminosugars such as glucosamine, including derivatives or pharmaceutically acceptable salts thereof, such as N-acetyl glucosamine sulfate, glucosamine hydrochloride, or glucosamine sulfate; certain vitamins and derivatives or salts thereof such as Vitamin C (e.g., ascorbic acid), Vitamin B (e.g., thiamin hydrochloride, thiamin mononitrate, Vitamin B6, Vitamin B12, niacin, biotin, folic acid, pantothenic acid), dried powder forms of Vitamin A, Vitamin D, Vitamin E, Vitamin K, or beta carotene; certain amino acids such as arginine and derivatives thereof or salts thereof; or combinations thereof.
Preferably, the other therapeutic compound is present in the tablet in an amount equal to or less than about 97 weight percent, more preferably from about 0.5 weight percent to about 95 weight percent and most preferably from about 10 weight percent to about 95 weight percent, based on the total tablet weight.
With respect to the compactability properties of a therapeutic compound, one skilled in the art will recognize that a therapeutic compound in one form may enhance the compactability of another therapeutic compound and/or be compactable, but in another form (such as crystalline) may not enhance compactability of a therapeutic compound. As such it is possible that a therapeutic compound in two different forms could be formulated in a single tablet that is substantially free of excipients. However, the tablet should contain at least one therapeutic compound that is chemically different from the compaction enhancing therapeutic compound. For example, the tablet may contain two different compaction enhancing therapeutic compounds and no other therapeutic compounds; one compaction enhancing therapeutic compound and one or more non-compaction enhancing therapeutic compounds; or one or more compaction enhancing therapeutic compound and one or more non-compaction enhancing therapeutic compounds.
The compaction enhancing therapeutic compound and the other therapeutic compound are formed into a compactable granular mixture. By xe2x80x9ccompactable,xe2x80x9d it is meant that the granular mixture is capable of forming a 500 mg sized round tablet having a diameter of {fraction (7/16)}xe2x80x3 (standard concave) at a compaction pressure of greater than about 1000 lbs and having a hardness of at least about 5 Strong Cobb (SC) and a friability of less than about 1%. Preferably, the compactable granular mixture will be freely flowable for tabletting. Preferably, the compactable granular mixture will have a particle size distribution of 95 percent by weight of the particles passing through a 20 mesh screen and less than 50% by weight of the particles passing through a 100 mesh screen (standard US mesh size).
One skilled in the art will recognize that there are various ways to form a compactable granular mixture. Any method may be used for combining the therapeutic compounds and other desired additives (e.g., excipients) that results in a compactable granular mixture. For example, a compactable granular mixture may be formed by blending the compaction enhancing therapeutic compound, the other therapeutic compound, and any other additive as a dry blend. A compactable granular mixture may also be formed by granulating a mixture containing the compaction enhancing therapeutic compound and other therapeutic compound. A compactable granular mixture may also be formed by at least partially or completely dissolving the compaction enhancing therapeutic compound and other therapeutic compound in a suitable liquid, followed by removal of the liquid. It may also be necessary, as hereinafter described, to subsequently process the mixture formed (e.g. pulverize, agglomerate) after combining the therapeutic compounds to form the compactable granular mixture
One skilled in the art will recognize that the desired method chosen for forming a compactable granular mixture will depend upon, for example, the selection of the compaction enhancing therapeutic compound, the other therapeutic compound, and any other desired additive. For example, as explained in further detail hereinafter, it may be necessary, based on the selected therapeutic compounds, to form granules containing an intimate admixture of at least a portion of the compaction enhancing therapeutic compound and at least a portion of the other therapeutic compound to form a compactable granular mixture. However, it may also be possible that certain compaction enhancing therapeutic compounds may simply be mixed with the other therapeutic compound to form a compactable granular mixture.
By xe2x80x9cintimate admixture,xe2x80x9d it is meant that the compaction enhancing therapeutic compound is uniformly admixed at a molecular level with the other therapeutic compound (e.g., in the case of at least partially dissolving both therapeutic compounds in a fluid, and removing the fluid), and/or admixed in a manner so that discrete particles containing the compaction enhancing therapeutic compound or a solid film containing the compaction enhancing therapeutic compound are in at least partial contact with the surfaces of the particles containing the other therapeutic compound. In a preferred embodiment, the compaction enhancing therapeutic compound is at least partially coated as a solid film onto the surfaces of the other therapeutic compound.
There are various ways in which granules containing an intimate admixture of the compaction enhancing therapeutic compound and the other therapeutic compound may be formed. For example, granules of an intimate admixture of the therapeutic compounds may be prepared by wet granulating or solvent dissolution and removal process methods. In some circumstances, dry granulating may be used to form granules containing an intimate admixture of the therapeutic compounds. xe2x80x9cGranulatingxe2x80x9d as used herein refers to a process where two or more smaller particles are combined to form larger granule particles through such processes as extrusion, compaction, fluid-bed granulation, or tumbling. xe2x80x9cSolvent dissolution and removalxe2x80x9d as used herein refers to a process where solids are at least partially dissolved in a liquid, and then the liquid is removed to form a granular mixture (e.g., spray drying).
One skilled in the art will recognize that there are various ways to wet granulate the therapeutic compounds. Typically, the therapeutic compounds will be mixed in the presence of a granulating fluid, and wet granules containing an intimate admixture of the therapeutic compounds will be formed simultaneously with mixing, and/or subsequently through additional means. The wet granules containing the therapeutic compounds are then preferably dried and pulverized to a suitable particle size for tabletting.
There are various ways in which the granulating fluid may be added to the therapeutic compounds. For example, a dry blend may be formed containing the therapeutic compounds, and the granulating fluid may be added to the dry blend to form a wetted mixture of therapeutic particles. Alternately, one or more compaction enhancing therapeutic compounds may be dissolved or dispersed in the granulating fluid that is then added (e.g., by spraying) to a dry blend containing the other therapeutic compound to form a wetted mixture of the therapeutic particles.
One skilled in the art will also recognize that there are various ways in which to granulate the wetted mixture of therapeutic particles. For example, granules may be simultaneously formed while adding the granulating fluid to the therapeutic compound(s) with mixing, such as tumbling, vibrating or shaking. Also, granules may be formed by extruding the wetted mixture of therapeutic granules and/or particles through a die or screen to form larger granules in various shapes such as noodles, pellets, briquettes, spheres, or combinations thereof.
Suitable equipment for wet granulating is disclosed in for example Chemical Engineers"" Handbook, by Perry and Chilton, fifth edition, published by McGraw-Hill Inc., 1973, Chapters 8 and 19, the disclosure of which is hereby incorporated by reference in its entirety. In a preferred embodiment of the present invention, continuous granulation equipment is used such as a single screw or twin screw extruder. A preferred extruder is an extructor supplied by Rietz Manufacturing Company. Alternatively, batch equipment designed for the blending both solids and liquids may be used such as for example cone and screw mixers, double arm kneaders, twin blade conical mixers, planetary mixers, helical ribbon blade mixers, conical blenders, or combinations thereof.
The granulating fluid used for wet granulating may be water or any biocompatible solvent that is effective in forming granules containing an intimate admixture of the therapeutic compounds. In a preferred embodiment of the present invention, the granulating fluid is chosen so that the compaction enhancing therapeutic compound is at least partially soluble and more preferably completely soluble in the granulating fluid. Preferably also, the granulating fluid is selected so that the other therapeutic is at least partially insoluble.
The amount of granulating fluid added during granulation to form the wetted mixture of therapeutic particles will depend on such factors as the processing equipment chosen, the types of therapeutic compounds selected, the particle size of the therapeutic compounds, and length of processing time. Typically however the amount of fluid will be from about 5 weight percent to about 30 weight percent, and more preferably from about 8 weight percent to about 15 weight percent, based on the total weight of solids being granulated.
Examples of fluids that may be used include water, biocompatible organic solvents such as C1 to C4 alkyl alcohols, such as methanol, ethanol, n-propanol, isopropanol, or butanol; ethers such as alkoxylated ethers, alkyl ethers, diether, triethers, oligo ethers, polyethers, or cyclic ethers; ketones such as acetone or methyl ethyl ketone; alkyl acetates such as ethyl acetate; alkanes, such as C5 to C8 aliphatic alkanes such as hexane or heptane; cyclic hydrocarbons such as C5 to C6 cyclic hydrocarbons such as cyclopentane or cyclohexane; aromatic hydrocarbons and derivatives thereof such as toluene; or combinations thereof.
It is also possible to form the granulate mixture using a supercritical fluid as the granulating fluid. A supercritical fluid exists at conditions where its liquid and gaseous states are indistinguishable from one another. The critical temperature of a fluid is the temperature above which that fluid cannot be liquified by an increase in pressure. The critical pressure of a fluid is the pressure of the fluid at its critical temperature. Examples of useful supercritical fluids include carbon dioxide, or mixtures of carbon dioxide and aliphatic or cyclic alkanes.
The temperature and pressure at which wet granulation is carried out will depend on the therapeutic compounds and granulating fluid chosen. Preferably, when using water, wet granulation will be carried out at a temperature of from about 22xc2x0 C. to about 37xc2x0 C., and more preferably from about 22xc2x0 C. to about 30xc2x0 C. Typical granulation pressures through the die range from about atmospheric pressure to several thousand pounds per square inch (psi). In the case of using a supercritical fluid, wet granulation would be carried out at a temperature and pressure at which the fluid exists in a supercritical state.
Following wet granulation, at least a portion of the granulating fluid is removed from the wet granulate mixture to form a dry granulate mixture. The amount of fluid removed will depend on such factors as the total amount of granulating fluid added, selection of the therapeutic compounds, particle sizes of the therapeutic compounds, and the solubilities of the therapeutic compounds in the granulating fluid. Preferably, at least about 50 weight percent, and more preferably from about 80 weight percent to about 98 weight percent of the added granulating fluid in the wet granulate mixture is removed to form a dry granulate mixture. The drying temperature is preferably chosen to efficiently remove the granulating fluid without degrading the therapeutic compounds in the granulate mixture.
A granulate mixture may also be formed by at least partially dissolving, and more preferably completely dissolving the compaction enhancing therapeutic compound and the other therapeutic compound in a liquid, and removing the liquid by any suitable technique to form granules containing the therapeutic compounds in intimate admixture. The selection and amount of liquid used will depend on the solubilities of the therapeutic compounds.
Examples of suitable liquids include water, biocompatible organic solvents such as C1 to C4 alkyl alcohols, such as methanol, ethanol, n-propanol, isopropanol, or butanol; ethers such as alkoxylated ethers, alkyl ethers, diether, triethers, oligo ethers, polyethers, or cyclic ethers; ketones such as acetone or methyl ethyl ketone; alkyl acetates such as ethyl acetate; alkanes, such as C5 to C8 aliphatic alkanes such as hexane or heptane; cyclic hydrocarbons such as C5 to C6 cyclic hydrocarbons such as cyclopentane or cyclohexane; aromatic hydrocarbons and derivatives thereof such as toluene; or combinations thereof.
Any technique known to those skilled in the art for removing the liquid from the therapeutic compound may be used such as continuous dryers (e.g., spray, fluid bed, tube, Witte or tunnel dryers), or batch dryers (e.g., rotary, pan, vacuum, or microwave dryers). In a preferred embodiment, the liquid is removed by a spray dryer. The drying conditions (e.g., temperature and pressure) will depend on the selection of liquid and therapeutic compounds, and should be chosen so as to not degrade the therapeutic compounds.
It is also possible, depending on the compaction enhancing therapeutic compound chosen, and possibly the level of moisture present in the mixture being granulated, that dry granulation can be used to form granules containing an intimate admixture of the compaction enhancing therapeutic compound and other therapeutic compound. xe2x80x9cDry granulationxe2x80x9d refers to a granulation process where no external fluid is added during processing. In such an embodiment, preferably the therapeutic compounds being granulated contain a total of at least about 4 wt % moisture, more preferably from about 5 wt % to about 15 wt % moisture, and most preferably from about 6 wt % to about 10 wt % moisture, based on the total weight of the therapeutic compounds. Such moisture is preferably inherently present in the therapeutic compounds as supplied. Preferably, the moisture present is water. It is believed that having some moisture in the therapeutic compounds aids in achieving an intimate admixture during dry granulation.
Any technique known to those skilled in the art may be used for dry granulating that promotes the formation of an intimate admixture of the therapeutic compounds. For example, dry granulation may be accomplished by admixing the compaction enhancing therapeutic compound and other therapeutic compound in a suitable piece of mixing equipment, and/or using compaction equipment, such as a roll press, to compact the dry blend into a desired shape to form an intimate admixture. In a preferred embodiment, dry granulation is carried out using a Chilsonator(trademark) press.
The temperature and pressure at which dry granulation is carried out will depend on the therapeutic compounds chosen. Preferably, dry granulation will be carried out at a temperature of from about ambient to about 45xc2x0 C., and more preferably from about 20xc2x0 C. to about 30xc2x0 C.
Although it is preferred to form granules containing an intimate admixture of the compaction enhancing therapeutic compound and other therapeutic compound, it may be possible to simply blend the therapeutic compounds to form a compactable granular mixture. Any suitable equipment may be used to blend the therapeutic compounds including continuous or batch mixers suitable for mixing solids such as cone and screw mixers, twin blade conical mixers, planetary mixers, helical ribbon blade mixers, conical blenders.
To obtain a freely flowable compactable granular mixture, it may be desirable to further process the mixture containing the compaction enhancing therapeutic compound and other therapeutic compound prior to compressing into tablets. For example, when the therapeutic compounds are combined using wet or dry granulating methods, it may be desirable to further reduce the particle size of the coarse granules (e.g., noodles, pellets) obtained from such methods. Any suitable particle size reduction technique may be used that will provide the desired granulate particle size. Examples of suitable particle size reduction equipment is disclosed in for example Chemical Engineers"" Handbook, by Perry and Chilton, fifth edition, published by McGraw-Hill Inc., 1973, Chapter 8, the disclosure of which is incorporated by reference in its entirety. Preferred particle size reduction equipment includes a comil; a Fitz mill manufactured by the Fitzpatrick Company; delumpers; hammer mills or combinations thereof.
In the case of using solvent dissolution and removal techniques as previously described herein (e.g., spray drying), it may be desired to further increase the particle size of the granulate mixture. Any method known to those skilled in the art may be used to further agglomerate the granulate mixture, such as the wet granulation and dry granulation techniques previously described herein. Also, fluid beds, spheronization equipment, or rotating pans may used to agglomerate.
The compactable granular mixture that is compressed may contain low levels of excipients (i.e., additivies) as hereinafter described, or other therapeutic compounds, that are added after combining the at least one compaction enhancing therapeutic compound and other therapeutic compound by such techniques as granulation. In a preferred embodiment of the resent invention, at least a portion of the compaction enhancing therapeutic compound is wet granulated with at least a portion of the other therapeutic compound. Preferably, at least 5 eight percent, and more preferably at least 10 weight percent of the compaction enhancing therapeutic compound is granulated with at least 15 weight percent, and more preferably at east 30 weight percent of the other therapeutic compound. The remaining therapeutic compounds may be, for example, simply admixed after granulation.
In a preferred embodiment, the compactable granular mixture is prepared by wet granulating all the compaction enhancing therapeutic compound and all the other therapeutic compound by adding water in a high shear granulator or extractor, and drying the granules formed in a fluid-bed dryer, tunnel dryer, or tray dryer to obtain granules containing from about 0.5 weight percent to about 10 weight percent moisture, based on the total weight of the granules. The granules are then preferably milled through a Fitz mill equipped with a 20 U.S. standard mesh screen.
The compactable granular mixture formed is preferably in a freely flowable form for feeding into compression equipment to form tablets. Preferably, the flow of the compactable granular mixture is from about 5 to about 30 seconds through a funnel having an upper opening diameter of about 8.89 cm, a lower opening of about 1.11 cm, and a height from upper opening to lower opening of about 20.32 cm. Also preferably, the particle size distribution is such that 95 percent by weight of the particles pass through a 20 mesh screen and less than 50% by weight of the particles pass through a 100 mesh screen (standard US mesh size). Also, preferably, any fluids used in forming the compactable granular mixture are removed so that the mixture contains less than about 15 weight percent, more preferably less than about 10 weight percent, and most preferably less than about 8 weight percent moisture based on the total weight of the therapeutic compound.
In addition to the therapeutic compounds, the compactable granular mixture that is compressed to form a tablet may contain additives (i.e., excipients) in an amount of less than about 15 weight percent, based on the total weight of the compactable granular mixture (dry basis). Examples of additives that may be included in the compactable granular mixture are non-therapeutic binding agents, lubricants, diluents, disintegrants, glidants, absorbents, antiadherents, surfactants, coating agents, gelling agents, colorants, flavorants, or combinations thereof. One skilled in the art will recognize that some additives may serve a dual purpose in the tablet composition. For example, many cellulose containing compounds can serve as a binding agent, and diluent or disintegrant at high levels.
The additives may be added in any manner that provides a uniform dispersion of the additives in the compactable granular mixture that is compressed into tablets. For example, the additives may be added to one or more of the therapeutic compounds prior to, or during combining of the therapeutic compounds. For example, the additive may be mixed with the therapeutic compounds to form a dry blend prior to wet granulation or dry granulation. The additive may also be dissolved or dispersed in a liquid containing the therapeutic compounds prior to a solvent dissolution and removal process, or in a granulating fluid, optionally containing the compaction enhancing therapeutic compound prior to wet granulating. In such procedures, the additive is preferably part of the granule particles making up the granulate mixture. The additives may also be added subsequent to forming granules of therapeutic particles provided that the additive is uniformly dispersed in the compactable granular mixture prior to forming the tablet composition. For example, the additive may be blended as is with the granules of therapeutic compounds or may be dissolved or dispersed in a biocompatible liquid and applied to the granules of therapeutic compounds.
The preferred method of adding the additive will depend upon the additive. For example, binding agents,such as polyvinylpyrolidone (PVP) or hydroxypropylmethylcellulose are preferably added prior to, or during the forming of the granules containing the therapeutic compounds, so that the additive is part of the granule formed. Dry binding agents, such as microcrystalline cellulose, are preferably added subsequent to forming granules of the therapeutic compound. Also, for example, non-compaction enhancing therapeutic compounds, such as glucosamine, can be granulated with 5 wt % polyvinylpyrolidone, and mixed with a compaction enhancing therapeutic compound such as chondroitin that has a moisture content above 7 wt %. Some specific examples of additives useful in the method of the present invention are described below.
In a preferred embodiment of the present invention, the compactable granular mixture may contain less than about 10 weight percent, more preferably less than about 5 weight percent and most preferably from 0 to about 3 weight percent non-therapeutic binding agents based on the total weight of the compactable granular mixture (dry basis). Any binding agent that imparts cohesive strength to granules containing the therapeutic compounds or the compactable granular mixture may be used. Examples of non-therapeutic binding agents useful in the present invention include for example polyvinyl pyrrolidone; modified or unmodified starch; cellulose containing compounds such as hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), methylcellulose or ethylcellulose; polyalkyleneglycols such as polyethyleneglycol or polypropyleneglycol; gelatin; acacia gum; guar gum; sodium alginate; amylopectin, sorbitol; glucose; dextrin or combinations thereof. Preferred binding agents are polyvinyl pyrrolidone, HPMC, lower substituted HPC or combinations thereof.
The compactable granular mixture may also contain one or more lubricants to inhibit sticking of the granules or compactable granular mixture during processing. Preferably, the lubricant is present in the compactable granular mixture in an amount of from 0 weight percent to about 5.0 weight percent, and more preferably from about 0 to about 2.0 weight percent based on the total weight of the compactable granular mixture (dry basis). Examples of suitable lubricants include stearates such as stearic acid, palmitostearate, magnesium stearate, zinc stearate or calcium stearate; talc; hydrogenated vegetable oil; hydrogenated castor oil; liquid paraffin; surfactant; or combinations thereof.
The compactable granular mixture may also contain diluents that increase the bulk of the tablet. Examples of diluents useful in the present invention include for example sugars such as mannitol, sorbitol, or xylitol, lactose, dextrose, fructose, amylose, or sucrose; microcrystalline cellulose; ethyl cellulose; modified or unmodified starch; clays such as kaolin, alkaline earth metal carbonates, phosphates or sulfates such as calcium carbonate, magnesium carbonate, calcium phosphate, (e.g. di and tri basic calcium phosphate), calcium sulfate, or barium sulfate; magnesium trisilicate; aluminum hydroxide; or combinations thereof. The diluents preferably make up from 0 to about 15 weight percent, and more preferably 0 to about 10 weight percent of the compactable granular mixture (dry basis).
Disintegrants are used to facilitate the break-up of the tablet, after the tablet is administered to the patient. Preferably, the compactable granular mixture will contain from 0 to about 5 weight percent and more preferably from about 0.5 weight percent to about 2.0 weight percent disintegrants based on the total weight of the compactable granular mixture (dry basis). Examples of disintegrants useful in the present invention include modified or unmodified starches such as corn starch, potato starch, or wheat starch; croscarmellose, clays; cross-linked polyvinyl pyrrolidone; cellulose containing compounds, gums, algins, surfactant, HPC, or combinations thereof.
Coating agents are applied to the surfaces of the formed tablet and provide, for example, reduced future friability and ease of swallowability. Preferably, the amount coating agent is from about 0.5 wt % to about 6.0 wt % and more preferably from about 1.0 wt % to about 5.0 wt % based on the total weight of the compactable granular mixture (dry basis). Examples of suitable coating agents include cellulose containing compounds such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose or ethylcellulose; polyalkyleneglycols such as polyethyleneglycol or polypropyleneglycol; or combinations thereof.
The compactable granular mixture may also contain wetting agents, colorants, flavorants or combinations thereof. These additives preferably make-up from about 0.1 weight percent to about 10 weight percent, and more preferably from about 0.3 weight percent to about 5 weight percent of the compactable granular mixture (dry basis). Examples of suitable wetting agents include sodium dodecyl sulphate, sodium lauryl sulphate, polyoxyethylene sorbitan fatty acid esters (e.g., Tween(trademark) compounds), polyoxyethylene stearates, sorbitan fatty acid esters or combinations thereof. Suitable colorants include for example red beet powder, ferric oxides, FD and C dyes or combinations thereof. Flavoring agents useful in the present invention include for example fruit flavors, or sweeteners such as sodium saccharin, aspartame, confectionary sugar, sorbitol, sucrose, xylitol, or combinations thereof.
The compactable granular mixture thus prepared in accordance with the method of the present invention is compressed into a tablet according to any technique known to those skilled in the art. For example, in compacting the compactable granular mixture, the compactable granular mixture can be added to a die, and compressed into a tablet having the desired shape and weight. Prior to adding the compactable granular mixture to the die, it may be desirable to apply an external lubricant to the wall of the die. Examples of external lubricants useful in the method of the present invention include talc; starch; stearates such as magnesium stearate; hydrogenated vegetable oil; surfactant or combinations thereof
Preferably the compactable granular mixture is compressed at any suitable pressure and temperature to form a tablet having the desired properties such as strength, hardness, disintegration and release of the therapeutic compounds upon administration. Preferably, the compaction conditions are such that there is no degradation of the therapeutic compounds. Also, preferably, the compaction conditions are below the melting points of the therapeutic compounds to prevent lower tablet hardness or other tabletting process problems (e.g. glazing). Typical compaction pressures range from about 1000 lbs to about 10,000 lbs, and more preferably from about 4,000 lbs to about 8,000 lbs, where lbs is pounds force. Typical compaction temperatures range from about 15xc2x0 C. to about 60xc2x0 C. and more preferably from about 20xc2x0 C. to about 40xc2x0 C.
The tablets thus produced may be further processed as desired. For example, the tablet may be coated according to any technique known to those skilled in the art. Suitable coatings include those compounds previously described as being useful as coating agents for the compactable granular mixture. The tablets may also be enteric or regularly polished with such compounds as Carnuba wax.
The tablet compositions useful in the present invention contain preferably from about 3 weight percent to about 99.5 weight percent, more preferably from about 5 weight percent to about 50 weight percent, and most preferably from about 5 weight percent to about 15 weight percent of at least one compaction enhancing therapeutic compound, based on the total weight of the tablet composition. The tablets also preferably contain from about 0.5 weight percent to about 97 weight percent, more preferably from about 10 weight percent to about 95 weight percent, and most preferably from about 40 weight percent to about 95 weight percent of at least one second therapeutic compound that is different from the compaction enhancing therapeutic compound, based on the total weight of the tablet composition. The compaction enhancing therapeutic compound is preferably in intimate admixture with the second therapeutic compound. More preferably, the compaction enhancing therapeutic compound at least partially coats particles of the second therapeutic compound.
The tablet composition thus produced also preferably contains less than about 15 weight percent, more preferably less than about 8 weight percent, and most preferably less than about 2 weight percent excipients, based on the total weight of the tablet composition (dry basis). The excipients may be any of the additives previously described herein that are present in the compactable granular mixture and in the amounts previously described for the compactable granular mixture. Preferably, excipients that serve as a lubricant are present in the tablet composition in an amount of no more than 0.5 weight percent based on the total weight of the tablet composition.
The overall weight of the tablet ranges from about 100 mg to about 2000 mg, and more preferably from about 450 mg to about 1600 mg.
One skilled in the art will recognize that the tablet compositions made in accordance with the methods of the present invention can be used for a variety of purposes. For example, the tablets may be formulated to provide treatment of connective tissue, such as to prevent, repair, or lessen ailments of the joints and cartilage tissue, such as observed with arthritis. The tablet compositions may also be prepared to treat ailments of the skin such as hardening, roughening, aging, or wrinkling of the skin. The tablet compositions may also be prepared to provide to a patient nutritional supplements of vitamins, minerals, antioxidants, or to function as an appetite suppressant, analgesic, anti-smoking libido, or combinations thereof. The tablet compositions may also be prepared to enhance the emotional well being of a patient through for example herbal based extracts. The tablet compositions of the present invention may also be prepared to treat ailments such as viral, fungal, or bacterial infections, diseases, or injuries to the body.
There are many advantages to the tablet compositions prepared in accordance with the methods of the present invention. For example, by the tablet compositions being substantially free of excipients, smaller (in weight and volume) tablets can be prepared containing the same amount of therapeutic compound. By decreasing the excipients present in the tablet, the tablets prepared according to the method of the present invention can be more easily ingested, and/or formulated to contain more therapeutic compound(s) in a single tablet. By being able to increase the amount of therapeutic compounds in a single tablet, one reduces the need to ingest multiple tablets at a single time and/or multiple doses of the same product. Additionally, the reduction of excipients in tablets is beneficial to hyper-allergenic patients and also has a very positive effect on diurnal consumer compliance.
In a preferred embodiment of the present invention, the tablet composition made in accordance with the methods of the present invention contains from about weight percent 3 to about 80 weight percent, and more preferably from about 30 to about 60 weight percent of at least one glycosaminoglycan; from about 3 weight percent to about 95 weight percent, and more preferably from about 5 weight percent to about 70 weight percent of at least one amino sugar; and less than about 2 weight percent, and more preferably less than about 0.5 weight percent of excipients based on the total weight of the tablet (dry basis). Preferably, the amino sugar is glucosamine, or a derivative or pharmaceutically acceptable salt thereof and the glycosaminoglycan is chondroitin or a derivative or pharmaceutically acceptable salt thereof.
In this preferred embodiment, other therapeutic compounds may be present in the tablet composition such as manganese ascorbate, sodium ascorbate, calcium ascorbate, Vitamin C (i.e., ascorbic acid), dried powder forms of Vitamin A, Vitamin D, Vitamin E, Vitamin K, or beta carotene; vitamin B6, niacin, phosphorous containing salts, zinc containing salts, copper containing salts, calcium containing salts such as calcium citrate, calcium carbonate, oyster shell, magnesium, manganese sulfate, boron, estrogen(s), or combinations thereof. Preferably calcium is present in an amount of from about 7 weight percent to about weight percent; and the vitamin C is preferably present in an amount of from about 1 weight percent to about 10 weight percent, based on the total weight of the tablet composition (dry basis).
Also preferably in this embodiment, the overall weight of the tablet ranges from about 100 mg to about 2000 mg, and more preferably from about 500 mg to about 2000 mg. The aminosugar is preferably present in an amount of from about 250 mg to about 1000 mg, and the glycosaminoglycan is preferably present in an amount of from about 200 mg to about 1000 mg. Any excipients are preferably present in an amount of less than about 50 mg.
The above preferred tablet composition containing an aminosugar and glycosaminoglycan is particularly useful for the treatment of connective tissues. Other preferred compositions that can be formed into a tablet in accordance with the method of the present invention are those compositions disclosed in for example U.S. Pat. Nos. 5,364,845 and 5,587,363 both to Henderson, the disclosures of which are hereby incorporated by reference in their entireties.